Our long term goal is to define the determinants of lung water and solute exchange. We will test hypotheses by the lung micropuncture technique which through new measurements has led to new concepts of microvascular pressure, interstitial pressure and filtration rate. In this proposal, these measurements will be extended and new measurements will be developed in the isolated, perfused and the intact lung preparations. A major experiment concerns the measurement of microvascular barrier properties (hydraulic conductivity and reflection coefficient) by the split-drop technique, in single microvessels. These measurements will test the hypothesis that the control of microvascular permeability differs in arterioles and venules. In addition, the concept of filtration across large pulmonary vessels will be tested by a catheterization technique. Several experiments are planned to test the hypothesis that pressures and chemical composition of the interstitium are crucial determinants of lung liquid exchange. Thus, the effects of lung dehydration and increased alveolar surface tension on interstitial pressure will be determined. For the first time nanoliter volumes of interstitial liquid will be collected from arteriolar and venular sites for analysis of fractional and total protein concentrations. These analyses will allow an accurate estimate of protein osmotic pressure of interstitial liquid in different lung regions. Another new experiment will be to define the role of lung glycosaminoglycans (especially hyaluronate), which are constituents of the interstitial matrix, on lung microvascular filtration. A major advance of the lung micropuncture technique will be the establishment of the open-thorax, anesthetized rabbit preparation for intact lung micropuncture. In this preparation, the distribution of microvascular and interstitial pressures in hypoxia and hyperoxia will be explored. In separate experiments, we will test the notion that blood flow determines the distribution of microvascular pressures, and that in each vascular segment, blood velocity correlates with microvascular pressure. In addition, we will determine the attenuation of the pressure pulse from the pulmonary artery to the microvascular segment. Using the filtration and interstitial pressure data, computer models will be constructed to estimate membrane and interstitial coefficients which determine filtration for whole lung. The results of our investigations will elucidate fundamental mechanisms in the regional control of lung microvascular permeability and will promote our understanding of the fundamental processes of pulmonary edema.